Tag Archive for: brain tumor

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat His Own Glioblastoma

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Al Musella, DPM
President, Musella Foundation For Brain Tumor Research & Information, Inc.

Two years ago, our Curious Dr. George asked Al Musella, DPM, what he would do if he were diagnosed with glioblastoma multiforme (GBM). Here, he revisits that question. Dr. Musella is President of the Musella Foundation For Brain Tumor Research & Information, Inc.

Curious Dr. George: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with GBM?

Dr. Musella: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me—a newly diagnosed GBM in an adult in otherwise good shape. There are several choices:

Standard of Care: Surgery, radiation, and the drug temozolomide; with this standard approach, the chance of 5-year survival is about 5%. However, standard of care plus Optune—a wearable device that uses electrical fields to treat GBM—bumps my chance of 5-year survival up to 24.9% (if used over 90% of the time) with no added toxicity.

Phase 3 Clinical Trials: There are now about four phase 3 trials for newly diagnosed GBM in the U.S. One involves intraoperative radiation therapy at the time of the initial surgery and looks worthwhile. The others involve treatments that in earlier trials improved survival by just a few months. They may be worth a try if they did not have two big downsides: 1) Most have a control group of patients who receive the old standard of care so that some of the participants do not get the experimental treatment. 2) Some do not allow you to use Optune, so you are trading a known benefit for a chance at an unknown benefit.

Historically, over the last 50 years or so, only a handful of phase 3 trials have been successful. Optune was the most successful phase 3 trial, and no other phase 3 trial has yet come close, so the chances of doing better in a phase 3 trial than Optune is low. What we thought were the most promising phase 3 trials over the last few years all failed. We are waiting for results from the phase 3 trial of DcVax—that may be a game changer, but this therapy is not available to the public right now.

Phase 1 or 2 Trials: About 150 phase 1 or 2 trials are currently active in the U.S. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials, some of which are better than those seen with standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not (under the current system) have the ongoing results of these trials—we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments.

Off-Label Use of Drugs Approved for Other Diseases: There are many choices here, and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.

Cocktail Approach Involving Experimental and FDA-Approved Treatments: Right now, this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments tried, and the outcomes so we can learn from every patient.

Getting Access to Experimental Therapies: There are a few pathways to getting experimental therapies. Currently, none are really practical on a large scale. I have tried to get expanded access/compassionate use/right-to-try access on the most promising experimental treatments, and it is very hard. Getting multiple drugs this way for a cocktail is just about impossible. We had high hopes for the Right To Try Act, which was passed last year, but it turned out not to help at all. Drug companies are not willing to use this pathway for brain tumor patients. However, even if we could get them, without tracking the results, we are not learning and are doomed to repeating the same failures.

My foundation is  working on a new bill that will solve this problem and speed up the search for the cure. Click here to learn more.

So, bottom line: What would I do?

Surgery: I would begin with surgery, trying for maximal safe resection, possibly using Gliolan (a dye that helps surgeons see small clusters of GBM cells) to increase chances of maximal resection. I would also consider insertion of Gliadel wafer (intraoperative chemotherapy) if the resection cavity is not up against the ventricles (and we are not planning on entering a trial that excludes prior use of Gliadel) or some type of intra-operative radiation.

Radiation: I would receive standard radiation or possibly proton beam radiation. This may be followed by some type of boost, possibly “leading-edge” radiosurgery.

Temozolomide: I would receive this drug during and after radiation, only if molecular testing of my tumor sample detects methylated MGMT. If the tumor is unmethylated, I would seek treatment with the drug Val-083, either in a trial or through a compassionate use/right-to-try program. The length of time to use temozolomide is controversial. The most commonly uses length of treatment is 6 months after radiation (as well as during radiation).

Immunotherapy: There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine and gene therapy trials have tails of 20% or more of patients living over 5 years and with minimal or no side effects. I would try to get one (or maybe two) of these drugs. The polio vaccine trial (PVSRIPO) looks promising, as does the CMV vaccine, the Survaxin vaccine, and Gliovac.

Optune: We are put into a very tricky situation here. Many trials will disqualify you if you use Optune, but Optune has the highest survival rates in large trials. So as I said before, you are being asked to gamble a known benefit for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. The results with Optune alone are still not good enough. The results shown above were for newly diagnosed GBMs. For recurrent GBMs, they are not nearly as good, so it is important to use it early in the course of the disease. Ideally, I would combine Optune with one of the immunotherapy treatments in phase 2 or 3, but that is not possible yet. We really need to fix that. Why should I be allowed to die just to appease an archaic tradition of requiring standard phase 2 and 3 trials?

…The choices are overwhelming for me. And for someone new to brain tumors, it is impossible to decide. We—the Musella Foundation—have formed a collaboration with Cancer Commons to create a program to help patients find the best treatment options for their individual case, then help them get access. We track how these patients do so that we learn from every patient. To take advantage of this free program, click here.

Dr. Musella can be reached at musella@virtualtrials.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Facilitating Access to Treatment for Children with Brain Cancer

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Leslie Jared, RN, MSN

A Q&A with Leslie Jared, RN, MSN, Nurse Navigator at Cancer Commons. Email: leslie.jared@cancercommons.org

Q: A midline glioma is a type of brain tumor that is particularly dangerous because of its nature and its location in the brain. It often afflicts children. An investigational drug called ONC201 has shown early promise in some patients whose tumors have a specific genetic mutation called H3 K27M. At Cancer Commons, in collaboration with xCures and Oncoceutics (the developers of ONC201), we are helping patients who cannot participate in ongoing clinical trials with ONC201 to gain access to the investigational therapy. You work directly with some of the patients in this program. Can you update our readers on its progress?

A: Oncoceutics has several clinical trials in progress to evaluate ONC201 in high-grade glioma, in particular for patients with H3 K27M-mutant glioma. The expanded access program currently allows the treatment of patients in the U.S. with recurrent/progressive H3 K27M-mutant and/or midline high-grade gliomas that are not otherwise eligible to participate in these trials. This includes patients with diffuse intrinsic pontine glioma (DIPG).

Under expanded access, patients with life-threatening illnesses who are not eligible for clinical trials may access treatments that are still under investigation and have not yet been approved by the FDA. Access to investigational treatments does require review and authorization by the FDA, but more importantly, in order to be successful, it requires the active involvement and cooperation of drug companies, health care providers, and patient advocacy groups.

ONC201 is a highly selective antagonist of the dopamine receptor D2 (DRD2) and has shown the ability to cross the blood-brain-barrier. DRD2 is overexpressed in some forms of cancer, including brain tumors that possess the H3 K27M mutation. ONC201 has been shown to kill cancer cells via activation of an integrated stress response, inactivation of Ras signaling, and apoptosis (death of cells). Clinical trials have shown that ONC201 may benefit some patients with DIPG- and midline-glioma patients who exhibit the H3 K27M mutation.

H3 K27M-mutant glioma patients, including those with DIPG, who do not qualify for the currently enrolling ONC201 clinical trials can consider the ONC201 intermediate-sized expanded access program as an additional option. Unlike single-patient Compassionate Use protocols, the intermediate-sized Expanded Access Program allows the treatment of multiple patients under one protocol.

Oncoceutics opened the current Expanded Access Program in January 2019 under collaboration with xCures, The Al Musella Foundation, The Cure Starts Now and DefeatDIPG. Many physicians/institutions have been able to open the program and treat patients at their U.S.-based sites. The real-world safety and outcomes data for these expanded access patients is being collected in a clinical database and will be used in an effort to speed up the development process and provide broader learning on who can benefit from ONC201.

If you are interested in the ONC201 expanded access protocol for yourself or a loved one, I encourage you to register with Cancer Commons as a new patient. Once you complete the registration process, I will help guide you through the evaluation process to determine whether you or your loved one qualifies for the protocol.

Please note: Oncoceutics does not currently distribute ONC201 outside of the United States.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Leslie Jared, RN, MSN

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Fixed and Variable Factors that Impact a Brain Tumor Patient’s Prognosis

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A Q&A with Burt Nabors, MD, Professor and Director of the Division of Neuro-oncology at the University of Alabama, Birmingham, and a member of the Cancer Commons Brain Tumor Advisory Board; bnabors@uabmc.edu

Q: Primary brain gliomas can be devastating, often deadly, malignancies. Obvious prognostic factors include whether they are grade 1, 2, 3, or 4; their extent of growth prior to diagnosis (stage); and their location, such as in the brain stem. What are other key factors that affect prognosis? Some say that the skill of the original surgeon is the most important prognostic factor. Others suggest that the size (case volume) of the initial treating institution is most important. What do you think?

A: An excellent question and one I may try to answer in two ways. The first are the known and well-quantified prognostic factors. The two most powerful are the patient’s age and their performance status. Age is a pretty clear factor and one we cannot alter. We in the neuro-oncology community are seeing increased attention to treatment recommendations based on age, both at the young and older ends of the spectrum. These efforts do appear to provide brain tumor patients in those spaces improved outcomes. However, as a modifiable prognostic factor, age is not one.

A patient’s performance status is, at the core, a measure of how well they retain their station in life and can manage their activities of daily living independently. It most likely reflects the summation of several other factors, such as the location of the tumor, the grade, and the ability of the neurosurgeon to safely resect (remove) tumor. When looking simply at tumor location, we do see improved outcomes for tumors in the non-dominant hemisphere or in more silent regions, such as the frontal or anterior temporal lobes compared to more eloquent or vulnerable brain regions. However, again, the location of the tumor is not modifiable by the individual patient. It is where it is.

As you suggest, another—and modifiable—way to consider this question is to focus on the experience and skill of the neurosurgeon. I would submit the factors that have the greatest impact here are the training environment for the neurosurgeon, the experience and interest of the neurosurgeon in brain cancer, and the volume of the treatment facility. Surgery at centers involved in high volumes of brain tumor surgery with neurosurgeons who are dedicated to advancing the practice of surgical intervention is an important consideration.

The current practice of the neurosurgeon also has a significant impact on patient outcomes. This has been well quantified and published, clearly for high-grade glial tumors such as glioblastoma, but also for lower-grade tumors such as astrocytoma and oligodendroglioma WHO II. This need for a dedicated practice is typically seen in environments that offer pre-operative neurological function mapping, advanced imaging modalities, and intraoperative awake craniotomy with cortical mapping. When this degree of neurosurgical sophistication is available, it is often in settings with multidisciplinary groups, including a research base with an intense interest and focus on brain cancers.

An unfortunate current reality is that, most often, settings with this degree of sophistication are in our larger urban centers, where ease of access for patients living and presenting in a more rural environment can be quite a challenge. Creating opportunities to provide access and equal care to all remains a significant part of the neuro-oncology mission and challenge.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Options to Treat a Glioblastoma

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A Q&A with Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY; email: musella@virtualtrials.com, phone: 888-295-4740
Q: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with a glioblastoma multiforme (GBM)?
A: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me—a newly diagnosed GBM in an adult in otherwise good shape. There are several choices.

  1. Standard of care: Surgery, radiation, Temozolomide. Chance of 5 year survival is about 5%.
  2. Standard of care PLUS Optune. Bumps my chance of 5 year survival up to 24.9% (if used over 90% of the time) with no added toxicity.
  3. Phase 3 Clinical trials: There are now about nine phase 3 trials for newly diagnosed GBM. Some have impressive phase 1 and phase 2 data. By the time a treatment gets to phase 3, it has shown enough promise in earlier trials that the sponsor is willing to risk a lot of money to test in a phase 3 trial. Most have two big downsides: 1) Most have a control group of patients who receive the old standard of care so that some of the participants do not get the experimental treatment. 2) Most do not allow you to use Optune, so you are trading a known benefit for a chance at an unknown benefit.
  4. Phase 1 or 2 trials: There are about 75 of these trials in the USA. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials, which are much better than those seen with standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not (under the current system) have the ongoing results of these trials—we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments.
  5. Off label use of drugs approved for other diseases. There are many choices here and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.
  6. Cocktail approach involving experimental and approved treatments. Right now, this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments tried, and the outcomes so we can learn from every patient.

Getting Access to Experimental Therapies
There are a few pathways to getting experimental therapies. Currently, none are really practical on a large scale. I have tried to get expanded access/compassionate use/right-to-try access on the most promising experimental treatments and it is very hard. Last year, fewer than 1,000 patients were able to get FDA approval to try experimental drugs under the FDA’s expanded access program for all types of cancer. Getting multiple drugs this way for a cocktail is just about impossible. We had high hopes for the Right To Try act which was passed this year, but it turned out not to help at all. Drug companies are not willing to use this pathway for brain tumor patients. However, even if we could get them, without tracking the results, we are not learning and are doomed to repeating the same failures.
Marty Tenenbaum and I previously wrote about our ideas for solving this problem. See https://virtualtrials.com/fda2017.cfm
So – bottom line: What would I do?

  1. Surgery—trying for maximal safe resection, possibly using Gliolan (a dye that helps surgeons see small clusters of GBM cells) to increase chances of maximal resection, and insertion of Gliadel wafer (intraoperative chemotherapy) if the resection cavity is not up against the ventricles (and we are not planning on entering a trial that excludes prior use of Gliadel).
  2. Radiation—standard radiation or possibly proton beam radiation. Possibly followed by some type of boost. Possibly try adding a radiation enhancer like Trans Sodium Crocetinate, especially if there is residual tumor.
  3. Temozolomide—during and after radiation. Only if the tumor sample has methylated MGMT. If the tumor is unmethylated, I would try to get Val-083 either in a trial or on compassionate use/right to try. The length of time to use 3. temozolomide is controversial. There is finally a phase 3 trial comparing 6 months versus 12 months of temozolomide, but right now we really do not know which is best. Some doctors use it for as long as needed.
  4. There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine and gene therapy trials have tails of 20% or more of patients living over 5 years and with minimal or no side effects. I would try to get one (or maybe two) of these. The polio vaccine trial (PVSRIPO) is getting a lot of hype on “60 minutes” with some very impressive results on a small number of patients. I know the first patient in the trial, and she is doing great and tumor free 5 years after the treatment. [Disclaimer: I am on the patient advisory board of the brain tumor center at Duke, and helped fund the PVSRIPO Trial].
  5. Optune. We are put into a very tricky situation here. Many trials will disqualify you if you use Optune, but Optune has the highest survival rates in large trials. So as I said before, you are being asked to gamble a known benefit for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. The results with Optune alone are still not good enough. The results shown above were for newly diagnosed GBMs. For recurrent GBMs, they are not nearly as good so it is important to use it early in the course of the disease. Ideally I would combine Optune with one of the immunotherapy treatments in phase 2 or 3, but that is not possible yet. We really need to fix that. Why should I be allowed to die just to appease an archaic tradition of requiring standard phase 2 and 3 trials?

What would you do?
Al Musella’s contact info is included in the author affiliations at the top of this page.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.